DESCRIPTION: (Applicant's Description) Our proposal tests the hypothesis that host-reactive, bone marrow derived T-cells contribute significantly to acute GVHD by disruption of the thymic environment. We will employ approaches to distinguish mature donor inoculum T-cells from donor bone marrow derived T-cells and assess the differential effect of these cell populations. Our proposed studies will also determine whether novel cytokine antagonists positively or negatively impact on thymocyte development in the GVHD model. A future therapeutic emphasis in bone marrow transplantation will be directed toward cytokine antagonists as agents to prevent GVHD. Our studies may yield a better understanding of the cellular, cytokine and biochemical events that occur in the thymus during GVHD. Specific Aim 1: We will test the hypothesis that specific T-cell clones are important in the initiation and maintenance of GVHD. To test our hypothesis, we will utilize T-cell clones with specific Vbeta TCR expression (Vbeta3 and Vbeta6) which can react with host MIs antigens in the initiation and continuation of GVHD in a minor histocompatibility-mismatched murine bone marrow transplantation (BMT) model. The role of each of these T-cell populations as GVHD effectors will be assessed in target organ damage by positive and negative selection of the donor T-cell inoculum, in situ immunofluorescence staining, in vivo depletion with neutralizing antibodies and by adoptive transfer experiments. These studies will also be performed in a model system where GVHD occurs to minor H antigens. Specific Aim 2: We will test the hypothesis that antagonism of inflammatory cytokines, which have been shown to have an ameliorating effect on GVHD, could improve the thymic damage associated with GVHD. There is, however, evidence that IL-1 and TNF may have a physiological role in thymocyte development. Therefore, the effects of anti-IL-1R antibody and TNFR:Fc on thymic damage during GVHD, as well as their effect on normal thymocyte development, will be assessed. We will also determine whether the cytokines IL-11 and keratinocyte growth factor (KGF), known to protect the GI tract and epithelial cells, will indirectly influence the cytokine cascade and its impact on the thymus. Finally, the total body irradiation (TBI) dose can markedly increase GVHD. We also plan to assess in this section the impact of TBI dose on thymic function. Specific Aim 3: We will test the hypothesis that specific cellular and biochemical events account for damage to the thymus in GVHD. We will analyze the effects of GVHD on thymic differentiation, loss of negative selection, decrease in thymic cellularity, and the effects of cytokine cascades on thymic function. The thymic cellular events associated with GVHD will be correlated to the activity of mitogen-activated protein (MAP) kinases and critical DNA binding proteins that are thought to regulate thymocyte development.